title: A BAR domain-mediated autoinhibitory mechanism for RhoGAPs of the GRAF family.
abstract: The BAR (Bin/amphiphysin/Rvs) domain defines an emerging superfamily of proteins implicated in fundamental biological processes by sensing and inducing membrane curvature. We identified a novel autoregulatory function for the BAR domain of two related GAPs' (GTPase-activating proteins) of the GRAF (GTPase regulator associated with focal adhesion kinase) subfamily. We demonstrate that the N-terminal fragment of these GAPs including the BAR domain interacts directly with the GAP domain and inhibits its activity. Analysis of various BAR and GAP domains revealed that the BAR domain-mediated inhibition of these GAPs' function is highly specific. These GAPs, in their autoinhibited state, are able to bind and tubulate liposomes in vitro, and to generate lipid tubules in cells. Taken together, we identified BAR domains as cis-acting inhibitory elements that very likely mask the active sites of the GAP domains and thus prevent down-regulation of Rho proteins. Most remarkably, these BAR proteins represent a dual-site system with separate membrane-tubulation and GAP-inhibitory functions that operate simultaneously.
authors.affiliation: Institute of Biochemistry and Molecular Biology II, Heinrich Heine University Medical Center, Universitätsstrasse 1, 40225 Düsseldorf, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Eberth
authors.forename: Richard
authors.initials: R
authors.lastname: Lundmark
authors.forename: Lothar
authors.initials: L
authors.lastname: Gremer
authors.forename: Radovan
authors.initials: R
authors.lastname: Dvorsky
authors.forename: Katja T
authors.initials: KT
authors.lastname: Koessmeier
authors.forename: Harvey T
authors.initials: HT
authors.lastname: McMahon
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Ahmadian
mesh_terms: D002151:Calorimetry; D020690:GTPase-Activating Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D017434:Protein Structure, Tertiary; D020741:rho GTP-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D020690:GTPase-Activating Proteins; D020741:rho GTP-Binding Proteins